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The Journal of Neurophysiology Vol. 79 No. 4 April 1998, pp. 1653-1660
Copyright ©1998 by the American Physiological Society
1 Department of Clinical Neurophysiology, University Hospital, S-75185 Uppsala, Sweden; and 2 Department of Physiology I, University of Erlangen/Nürnberg, D-91054 Erlangen, Germany
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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Schmelz, M., R. Schmidt, A. Bickel, H. E. Torebjörk, and H. O. Handwerker. Innervation territories of single sympathetic C fibers in human skin. J. Neurophysiol. 79: 1653-1660, 1998. Microneurography techniques were used to record action potentials from unmyelinated nerve fibers (C fibers) in the cutaneous fascicles of the peroneal nerve in healthy volunteers. C units were identified by their long latency responses to electrical stimulation of their terminals in the skin. Their responsiveness to mechanical or heat stimuli applied to the skin or to sympathetic reflex provocation tests was determined by transient slowing of conduction velocity following activation (marking technique). In a sample of 381 C units, 59 were unresponsive to mechanical and thermal stimulation of their endings, but responded to sympathetic reflex provocation tests, e.g., arousal or deep inspiration. They were classified as sympathetic efferent units. On average, conduction velocities of sympathetic units were lower (0.78 ± 0.12 m/s, mean ± SD) than those of mechano-heat (CMH) or mechanoresponsive (CM) afferent C units (0.91 ± 0.14 m/s). Endings of most of the sympathetic units were located in the skin of toes or in the foot dorsum. Innervation territories of 16 sympathetic units were mapped by means of conditioning transcutaneous electrical stimuli. Twelve units had one continuous skin territory, whereas two units had two and two other units had three and five separate territories, respectively. The mean innervated area was 128 mm2 (range: 24-350 mm2). Innervation territories of sympathetic units were of approximately the same size in different skin regions on the lower leg, foot, or toes. Based on responses to whole body cooling and warming, two units were tentatively classified as vasoconstrictor and sudomotor units, respectively. Eleven units were tested for responsiveness to iontophoresis of acetylcholine in their innervation territories. In five of them, activity was induced that was not due to central reflex activity but instead due to antidromic activation from the peripheral terminals. Iontophoresis of saline or histamine was ineffective. These findings confirm the existence of excitatory cholinergic receptors in the terminal membrane of some sympathetic units, possibly sudomotors.
In 1967 Hagbarth and Vallbo first described recordings of spike activity from single myelinated nerve fibers in humans (Hagbarth and Vallbo 1967 Standard microneurography techniques were employed for recording from C fibers in cutaneous fascicles of the peroneal nerve dorsolateral to the fibular head in healthy subjects as described previously (Torebjörk 1974 Electrical search procedure
The search procedure for identifying single C units has been described before in detail (Schmidt et al. 1995 Marking
Responsiveness of single C units to different stimuli was ascertained by the "marking" phenomenon described in detail elsewhere (Hallin and Torebjörk 1974b
Stimulation maneuvers
Stimuli known to increase the skin sympathetic, sudomotor, and vasoconstrictor outflow in conscious humans were used to identify sympathetic efferents (Hagbarth et al. 1972 Mapping innervation territories
Innervation territories were mapped by conditioning electrical stimulation as described previously (Schmelz et al. 1994
Body warming and cooling
To classify the sympathetic efferents, the development of ongoing activity during whole body warming and cooling was studied in three experiments. Subjects were warmed by use of preheated blankets (40°C) and warm packs that were placed on thorax and abdomen for at least 30 min. Cooling was achieved by wetting the skin with ice water and increasing evaporation by directing an air stream from a fan to the wet skin. The leg from which the C fiber was recorded was excluded from these warming and cooling maneuvers. The effectiveness of these procedures was checked by measuring skin temperatures in the innervation territory, which decreased from a baseline level of ~30°C to values <25°C during the cooling procedure (35 min) and reached >33°C after 45 min of warming.
Iontophoresis
Because it has been assumed that the terminal membrane of sudomotor units contains excitatory cholinergic receptors responsible for axon reflex sweating (Coon and Rothman 1939 Identification of sympathetic C units
In a sample of 381 C units, 59 sympathetic efferents were identified by their responsiveness to sympathetic provocation tests. A typical example shown in Fig. 3 demonstrates clear increases in latency in association with sudden noise, the Valsalva maneuver, and during mental stress. Under control conditions (20-22°C room temperature, absence of arousal stimuli) most sympathetic efferents were spontaneously active (asterisk in Fig. 3). None of the sympathetic units showed responses to mechanical stimulation in the innervation territory. Conversely, none of the afferent C fibers investigated with identical techniques responded to sympathetic provocation tests.
Evidence against conduction block in sympathetic fibers at the recording site
This study employing the marking phenomenon provides information related to a recent controversy on the interpretation of microneurographic recordings. It has been suggested that conduction in most of the recorded units is blocked at the recording site (Wall and McMahon 1985 Innervation territories
To successfully map innervation territories of sympathetic C units, a fairly good signal-to-noise ratio and low level of ongoing discharge is necessary to reliably detect the spots from which the unit was antidromically activated, and hence determine the exact boundaries of the innervation territory. The units successfully mapped in this sample had a signal-to-noise ratio of at least 2:1 and an average ongoing activity of less than two "markings" per minute throughout the mapping procedure. Thirty-two of 59 units had lower signal-to-noise ratios or irregular spontaneous activity of higher frequency, which made the mapping unreliable, and they were not considered for further analysis. Another obvious prerequisite for successful mapping was a stable recording for this time-consuming procedure. In nine units the mapping was incomplete because the units were lost.
Classification of sympathetic units by their responsiveness during thermoregulation
In three experiments it was possible to assess thermoregulatory responses (to whole body warming and cooling) in sympathetic fibers after their innervation territories had been mapped. As expected, the temperature changes in the skin led to gradual and prolonged latency shifts of the C-unit responses due to changes of conduction velocity (Fig. 5). These gradual shifts were readily distinguished from the marking phenomenon, which is characterized by a transient increase in latency due to reflex activation. One unit had a conduction velocity of 0.78 m/s and a continuous innervation territory of 223 mm2. This unit showed almost no activity when the subject was warmed, whereas cooling markedly increased activity (Fig. 5). According to its activation pattern, the unit was tentatively classified as a vasoconstrictor unit. It should be noted that this unit still could be activated by arousal stimuli during the warming period. A second unit with a conduction velocity of 0.68 m/s and an innervation territory of 74 mm2 showed the opposite activation pattern by being depressed during cooling and activated during warming. The activation pattern of this unit is therefore consistent with a sudomotor or vasodilatator unit.
Responsiveness to iontophoresis of ACh
To test for excitatory cholinergic receptors in the terminal membranes, ACh was applied by iontophoresis (1 mA, 60 s; see METHODS) in the innervation territories of 11 sympathetic units. Five of the 11 units tested were clearly activated after termination of iontophoresis, which excludes a direct action of the current. Figure 6 shows an example. Activation typically started with a delay of a few seconds after termination of the current application and lasted for 3-5 min.
Use of the marking technique for analysis of activity in single sympathetic efferent units
The marking technique was originally developed to differentiate between electrically evoked afferent and sympathetic efferent C-unit responses in human skin nerves (Hallin and Torebjörk 1974b Bias in the present sample of mapped sympathetic units
Another obvious limitation of the marking technique is that units with a high level of spontaneous activity will be excluded from the analysis of innervation territories, because the ongoing barrage precludes stable latencies in response to intracutaneous electrical stimulation. The sample of 16 mapped sympathetic units reported here is thus biased in favor of units with low ongoing activity. Further evidence for this bias is that the mean ongoing activity was less than two markings per minute, which is lower than the mean discharge rates of single sympathetic fibers (9-36 imp/min) recorded in humans with conventional microneurography methods (Hallin and Torebjörk 1974a Innervation territories of sympathetic efferent units
The innervation territories of 16 sympathetic fibers were mapped by conditioning transcutaneous electrical stimuli. This mapping procedure was used in previous studies to analyze receptive-field organization of afferent C fibers that were responsive or unresponsive to mechanical stimuli (Schmelz et al. 1994 Action of ACh on sympathetic terminals
Five of 11 sympathetic units responded to iontophoretic application of ACh. This provides the first direct evidence that activation of cholinergic, probably nicotinic, receptors (MacMillan and Spalding 1969 Classes of sympathetic units in the skin
Sympathetic efferents to the skin of the leg and foot are functionally heterogeneous. Two groups of neurons have been identified, vasoconstrictor and sudomotor units (Bini et al. 1980
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
). Further refinement of the technique has allowed recordings of integrated multiunit activity from C fibers to study sympathetic outflow to muscle or skin (Hagbarth et al. 1972; Normell and Wallin 1974; Wallin et al. 1974). This technique has provided insights into autonomic regulation as well as pathophysiologic mechanisms of diseases like hypertension (Wallin 1989) and autonomic dysfunction (Wallin and Elam 1993).
, 1974a,b) or more recent (Macefield and Wallin 1996; Macefield et al. 1994) studies of single-unit recordings.
). Recently, a computer-assisted form of the marking technique was introduced, which increased the efficiency and power of resolution of this method (Schmelz et al. 1995; Schmidt et al. 1995).
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
). Recordings of activity in sympathetic units from 18 subjects (age range 21-29 yr) are reported in this paper. All subjects gave their informed consent, and the study was approved by the local ethics committees.
). Electrical stimuli (0.3 Hz, 0.3 ms, 40-100 V; delivered from a Grass S88 stimulator) were applied transcutaneously within the innervation territory of the impaled fascicle (lower leg or dorsum of foot) via a pointed steel electrode that was moved around on the skin, until a C-fiber response was obtained. At that site, two steel needles were inserted (5 mm apart) for intracutaneous electrical stimulation. Stimuli eliciting stable C-fiber responses were delivered at 4-s intervals (0.2-ms pulses of 10-40 V). These stimuli were well tolerated by the subjects over extended periods. They were described as slightly unpleasant, but not really painful. It is important to note that this technique works without recourse to mechanical stimulation of receptive fields that would limit the search to mechanosensitive afferent units.
; Schmelz et al. 1995; Schmidt et al. 1995; Torebjörk 1974; Torebjörk and Hallin 1974). The response latency to regular 0.25-Hz electrical stimulation of the nerve terminals is transiently increased if additional action potentials are induced in the respective axon. The membrane mechanism for the conduction slowing is not entirely clear. A relatively long-lasting hyperpolarization of the axon due to activity-dependent ion pumps has been suggested to account for the slowing of C fibers in rat (Thalhammer et al. 1994). Our group has demonstrated that increased response latencies are reliably detected even after interpolation of only one single action potential in afferent C fibers (Schmelz et al. 1995). Correspondingly, ongoing activity of sympathetic units is detectable in the continuous records of evoked activity (Fig. 1), although collisions between antidromic and orthodromic impulses may conceal the latency changes if the electrical stimulation frequency is high (Hallin and Torebjörk 1974b). As seen in Fig. 1, each transient latency shift may be caused by a variable number of impulses, implying that the marking technique can yield at best semiquantitative data on unit activation, but no exact measure of discharge frequency.
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FIG. 1.
Comparison of activity in a single sympathetic unit as shown in a conventional instantaneous frequency record (left) and with the "marking" method (right). In both diagrams the time course is from top to bottom. The spike responses to regular intracutaneous electrical stimulation at 4-s intervals are shown as regular line of dots in the instantaneous frequency diagram and as spikes in the diagram showing the marking. Additional conditioning stimuli are marked in the right diagram: open arrows indicate the lack of response to probing with a stiff von Frey hair; black triangle shows the lack of response to radiant heat application in the innervation territory of the unit (32-52°C). During heating the conduction, velocity of the units gets faster as can be seen from the marking display; this is not seen in the instantaneous frequency display because of its lower temporal resolution. During the 500-s recording period shown in this figure, one spontaneous burst of activity occurred ( 
) and another burst was induced by a loud noise (). The 1st burst consisted of 2 spikes, and the 2nd of 5 spikes, as shown in the instantaneous frequency display. Note that the bigger burst also induced more pronounced marking.
). A suitable time segment after the electrical test pulse was selected and displayed on the computer screen in succeeding traces from top to bottom (Figs. 3, 5, and 6) allowing on-line assessment of latency changes.
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FIG. 3.
Responses of a sympathetic unit to intracutaneous electrical stimulation at 4-s intervals. Successive traces are depicted from top to bottom. Probing with von Frey filaments exerting a force of 750 mN ( 
) did not activate the unit, as seen by the constant response latency to electrical stimulation. Spontaneous activity typical for sympathetic units caused shifts in latency without stimulation (*). Sympathetic provocation tests such as sudden noise, Valsalva maneuver (
) and mental stress by arithmetic tasks (vertical bar) induced shifts in response latency (marking) indicating activation of the unit. Response latency to electrical stimulation in the receptive field is indicated at bottom.
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FIG. 5.
Successive traces of responses of a sympathetic unit to intracutaneous electrical stimulation at 4-s intervals are shown from top to bottom. At right, 2 segments of the recording (A and B) are shown at higher (2 times) time resolution. Note that traces are highly condensed such that single spikes can no longer be recognized. Elevation of the subject's body temperature (black bar; see METHODS) caused a gradual decrease in response latency. The unit displayed relatively little ongoing activity (black dots in the expanded segment A) during the heating period. In contrast, cooling of the subject caused a gradual increase in response latency due to lower conduction velocity. At the end of the cooling period ongoing activity (black dots in expanded trace B) clearly increased. This pattern of activation (decrease of activity during heating, increase during cooling) suggests a vasoconstrictor unit.
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FIG. 6.
Successive traces of a sympathetic unit's responses to intracutaneous electrical stimulation at 4-s intervals are shown from top to bottom. Either saline (0.9%), or acetylcholine (ACh; 10%) was iontophoretically applied in the innervation territory at the dorsum of the foot. The iontophoresis period is indicated by bars on the left. No change in activity was observed after saline iontophoresis (left). In contrast, iontophoresis of ACh (right) clearly activated the unit as can be seen by the marked irregular increases in response latency.
; Hallin and Torebjörk 1970), i.e., unexpected loud noises, mental stress (by making rapid mathematical calculations), and inciting the subject to laugh or to inspire deeply. The efficacy of these maneuvers was verified by listening to the sympathetic multifiber background discharges from a loudspeaker. Mechanical and heating stimuli known to be suprathreshold for nociceptors were applied to the innervation territories of all efferent sympathetic units to test for possible excitability by natural stimulation. For mechanical stimulation a set of calibrated von Frey nylon filaments was used (Stoelting, Chicago, IL). Probing inside the innervation territory of sympathetic efferents with a stiff filament (750 mN) did not evoke discharges in any sympathetic unit. Heat stimuli were delivered from a halogen lamp controlled by feedback from a thermocouple attached to the skin (Beck et al. 1974). Skin temperature was increased by 0.25°C/s, from an adapting temperature of 32°C to a tolerance level of ~50°C at which point subjects terminated the stimulus. None of the sympathetic units showed a graded response to this kind of stimulus that typically activates polymodal afferent C fibers. Few of the sympathetic fibers showed irregular discharges usually starting 1-2 s after peak temperature and outlasting the stimulus for up to 10 s (not shown). These discharges probably were due to sympathetic reflex activity following painful stimulation. During this poststimulus period, heat-sensitive C afferents are always silent.
). The tip of a pointed steel electrode (1 mm2) was moistened with electrode gel and gently attached to the skin for focal electrical stimulation with the indifferent electrode (steel plate, 3 × 5 cm) placed on the lower thigh. Trains of three pulses were delivered from a constant current stimulator (Type 15E25 insulated stimulator output unit, Disa, Denmark) at a moderately unpleasant intensity (5-10 mA, duration 0.2 ms, interval 200 ms). To exclude activation of sympathetic efferents via a reflex induced by the mapping stimulus, the trains were time locked to the regular electrical pulses with an interval of 50 ms between the last of the three mapping pulses and the next regular pulse. The principle of this technique is shown in Fig. 2.
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FIG. 2.
Schematic diagram showing the experimental setup for mapping the innervation territory of sympathetic units. Intracutaneous electrical stimulation at 4-s intervals (black symbols; stim. 1) induces action potentials in a C unit that are conducted centrally and recorded at knee level (black symbols, response 1). Transcutaneous search stimuli (white symbols on black ground; stim. 2) are delivered via a pointed electrode. When these stimuli are applied inside the innervation territory (stim. 2a), an additional action potential is generated (white spike on black ground; response 2) that can be recorded at knee level. This extra spike causes a transient increase in response latency of the spike evoked by the regular intracutaneous pulse. If the mapping electrode is placed outside the innervation territory (stim. 2b), no extra impulses were elicited and no marking was seen. For purpose of clarity, just 1 extra pulse is illustrated in the figure. Normally trains of 3 search stimuli at an intratrain frequency of 5 Hz were applied through the mapping electrode.
), acetylcholine (ACh, 10% wt/vol in distilled water) was iontophoretically applied to the innervation territory of 11 units. The applicator was identical to a device that has been used for histamine iontophoresis by our group (Handwerker et al. 1987; Magerl et al. 1990) and also for iontophoresis of ACh in psychophysical experiments (Vogelsang et al. 1995). It had a diameter of 6 mm. A positive current of 1 mA was applied for 60 s, resulting in a transferred charge of 60 mC. Iontophoretic applications of saline (9 units) and histamine (4 units) were used as controls.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
2 test). Because all afferent and efferent units were searched with transcutaneous electrical stimuli, there was no regional bias that could explain this result.
, 1997).
). However, our results clearly show that sympathetic provocation tests cause a slowing of conduction velocity distal to the recording site in all sympathetic units. Because reflex activity in efferent fibers travels distally, action potentials of the units under study were apparently conducted across the recording site to the periphery without being blocked.
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FIG. 4.
Shapes and areas of innervation territories of 16 sympathetic efferents in 3 different regions of the leg. Complex territories innervated by the same parent C axon are connected by lines.
View this table:
TABLE 1.
Area and diameter of the 16 mapped sympathetic units found in the toes, the foot dorsum, and the lower leg
).
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
) and was used presently to study activity in single sympathetic efferent axons. Although this technique allows only qualitative or semiquantitative assessment of C-unit activity (Schmelz et al. 1995), it has the advantage of allowing long-term recordings from single units. Over recording periods of several hours, spike activity can be definitively allocated to a single axon based on the characteristic latency of that particular unit after electrical stimulation of its terminals. Because of the long conduction distance between fiber terminals in the foot or lower leg and the recording site at the knee level, superposition of spikes from different axons is rare.
, the probability of detecting antidromic activity in the centripetally conducted C response of sympathetic fibers will be reduced if the stimulation frequency is high, and if recordings are made at a long distance from the ganglion. We have tried to minimize these limitations by using low-frequency (0.25 Hz) stimulation and recording at knee level. However, measuring the response latency every 4 s reduces the temporal resolution of the method. Each marking indicates that one or more impulse occurred in the sympathetic fiber during the preceding 4 s, and the number of markings cannot exceed 15 per minute.
; Macefield and Wallin 1996). However, such a methodological bias may not necessarily be relevant to the entire sample of 58 sympathetic units. They were all searched by transcutaneous electrical stimuli in the same way as we searched for afferent C-fiber activity. Therefore we feel justified in comparing the innervation densities of afferent and efferent C fibers in different regions of the leg, and we thus suggest that the higher proportion of sympathetic efferents found in the toe region may be real and not a sampling artifact.
, 1996). In case of the CM or CMH sensitive units, the borders of the innervation territories determined by electrical stimulation were essentially identical with the borders of receptive fields determined by von Frey hair stimulation within a tolerance limit of ~2 mm. Therefore the transcutaneous electrical stimulation method probably yields reliable assessments of the terminal arborization of single cutaneous C units in relation to the skin surface. We found that extensions of the innervation territory did not follow the presumed trajectory of the parent axon in any of the sympathetic units, indicating that true innervation territories were mapped as projected onto the skin surface. However, we cannot exclude the possibility that deep branches of afferent as well as efferent C units were not detected by our transcutaneous stimulation procedure. In two units, quite strong transcutaneous electrical stimuli were ineffective, whereas intracutaneous stimulation was effective. Presumably these units innervated deeper structures. Interestingly, the innervation territories of sympathetic units that could be mapped were of the same order of magnitude as those of afferent CM and CMH units, although the tendency toward smaller innervation territories in more distal parts of the foot, which we observed for the afferent units (Schmidt et al. 1997), was not presently observed for efferent units.
) in the terminal membrane of sympathetic units induces prolonged, antidromic neuronal discharges. They might then pass orthodromically into axon collaterals, a prerequesite for axon reflex sweating. It has been shown that an identical stimulus applied to the skin of the foot dorsum induces axon reflex sweating that covers an area with a median radius of 26 mm in the direction of its greatest extension (Riedl et al. 1998). This radius fits well with the mean diameter of innervation territories of sympathetic units encountered in this study (median maximal diameter: 21 mm). The fit between the mean extension of the sweating response and the innervation territory of the sympathetic units assessed in this study provides further evidence for the accuracy of our mapping technique. Iontophoresis of saline or histamine did not activate sympathetic units, in accordance with the finding that axon reflex sweating is induced by ACh, but not by histamine (Benarroch and Low 1991; Riedl et al. 1998).
). However, sympathetic vasodilator units have been found in animal (Bell et al. 1985; Gregor et al. 1976) and human (Lundberg et al. 1989) skin, and their possible contribution to axon reflex vasodilatation cannot be excluded. There is no indication that ACh also induces axon reflex vasoconstriction in the skin; however, this might be masked by the concurrent vasodilatation. ACh or nicotine evokes the release of noradrenaline from sympathetic terminals in the walls of arteries in animal preparations (Bultmann et al. 1991; Niedergaard and Schrold 1977). This indicates the existence of nicotinic receptors in at least some vasoconstrictor terminals associated with vasculature, although the mechanism does not necessarily involve antidromic spike activity. Therefore it is presently uncertain whether the ACh test will provide a tool to differentiate between sudomotor and vasoconstrictor efferents.
; Normell and Wallin 1974). As mentioned above, there is evidence that also vasodilators exist in animal (Bell et al. 1985; Gregor et al. 1976) and human (Lundberg et al. 1989) skin. However, the vasodilators found by Jänig and co-workers in cat hairy skin (Bell et al. 1985; Gregor et al. 1976) were not contributing to sympathetic arousal reflex activity, whereas all of the present sympathetic efferents did.
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ACKNOWLEDGEMENTS |
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We thank Prof. Earl Carstens for helpful comments and for improving the style of the manuscript.
This work was supported by the Bank of Sweden Tercentenary Foundation (to H. O. Handwerker), the Max Planck Award for International Cooperation (to H. E. Torebjörk), the Swedish Foundation for Brain Research (grant to R. Schmidt), the Swedish Medical Research Council, Project 5206, and the Deutsche Forschungsgemeinschaft (SFB 353).
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FOOTNOTES |
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Address for reprint requests: M. Schmelz, Institut für Physiologie und Experimentelle Pathophysiologie, Universitätsstr. 17, 91054 Erlangen, Germany.
Received 20 February 1997; accepted in final form 17 December 1997.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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